1.6 - Pharmacology of depression (core drugs)

Question 1

What is the role of serotonin in the central nervous system?

Answer 1

Plays a role in regulation of mood, personality and wakefulness

Question 2

What are the five classes of antidepressants?

Answer 2

• sertraline
• citalopram
• fluoxetine
• venlafaxine
• mirtazapine

Question 3

What are the three most commonly prescribed selective serotonin reuptake inhibitors (SSRIs)?

Answer 3

• sertraline
• citalopram
• fluoxetine

Question 4

What is the primary mechanism of action of sertraline?

Answer 4

Inhibition of serotonin reuptake results in serotonin accumulation

Question 5

What is the drug target of sertraline?

Answer 5

Serotonin transporter

Question 6

What are the main side effects of sertraline? (4)

Answer 6

• GI effects (nausea, diarrhoea)
• sexual dysfunction
• anxiety
• insomnia

Question 7

What is some extra information about sertraline?

Answer 7

• mild inhibition of dopamine transporter
• must be gradually decreased on discontinuation
• partial inhibition of CYP2D6 at high doses (150mg)

Question 8

What is the primary mechanism of action of citalopram?

Answer 8

Inhibition of serotonin reuptake results in serotonin accumulation

Question 9

What is the drug target of citalopram?

Answer 9

Serotonin transporter

Question 10

What are the main side effects of citalopram? (5)

Answer 10

• GI effects (nausea, diarrhoea)
• sexual dysfunction
• anxiety
• insomnia
• prolonged QT interval

Question 11

What is some extra information about citalopram?

Answer 11

• mild antagonist of muscarinic and histamine (H1) receptors
• must be gradually decreased on discontinuation
• metabolised by CYP2C19

Question 12

What is the primary mechanism of action of fluoxetine?

Answer 12

Inhibition of serotonin reuptake results in serotonin accumulation

Question 13

What is the drug target of fluoxetine?

Answer 13

Serotonin transporter

Question 14

What are the main side effects of fluoxetine? (4)

Answer 14

• GI effects (nausea, diarrhoea)
• sexual dysfunction
• anxiety
• insomnia

Question 15

What is the primary mechanism of action of venlafaxine?

Answer 15

• more potent inhibitor of serotonin reuptake than norepinephrine reuptake
• noradrenaline is involved in regulation of emotion and cognition

SNRI

Question 16

What are the drug targets of venlafaxine?

Answer 16

• serotonin transporter
• noradrenaline transporter

Question 17

What are the main side effects of venlafaxine? (5)

Answer 17

• GI effects (nausea, diarrhoea)
• sexual dysfunction
• anxiety
• insomnia
• hypertension (at higher doses)

Question 18

What is some extra information about venlafaxine?

Answer 18

Must be gradually decreased on discontinuation

Question 19

What is the primary mechanism of action of mirtazapine?

Answer 19

• antagonises central presynaptic alpha-2-adrenergic receptors
• causes increased release of serotonin and noradrenaline
• antagonises central 5HT2 receptors, leaving 5HT1 receptors unopposed causing anti-depressant effects

Question 20

What are the drug targets of mirtazapine?

Answer 20

• alpha-2 receptor
• 5HT2 receptor

Question 21

What are the main side effects of mirtazapine?

Answer 21

• weight gain
• sedation

Question 22

What is some extra information about mirtazapine?

Answer 22

• low probability of sexual dysfunction
• may exacerbate REM sleep behaviour disorder

Question 23

What anti-depressant should you avoid if you are already on a drug associated with QT prolongation (like erythromycin)?

Answer 23

• citalopram - severe interaction
• also: increasing age, female sex, cardiac disease and some metabolic disturbances (notably hypokalaemia) predispose to QT prolongation

Question 24

If we assume that the anti-depressant effects of SSRIs are solely due to their action at the serotonin transporter, how do we explain the plateau in therapeutic effect?

Answer 24

The serotonin reuptake transporters become fully blocked and concentration of serotonin in synapse becomes maxed out

Question 25

Why do you have to slowly wean off one antidepressant before starting a new one?

Answer 25

Caution is required when switching from one antidepressant to another due to the risk of drug interactions, serotonin syndrome, withdrawal symptoms or relapse

Question 26

At very high doses, what effect can mirtazapine have?

Answer 26

Anti-emetic effect (acts on 5HT3 receptor)

Question 27

Describe how changing the dose of mirtazapine can change the response produced.

Answer 27

• at low doses, mirtazapine preferentially blocks the histamine receptor since at lower plasma concentrations it has higher affinity to H1 than serotonergic receptors
• consequently, there is increased duration of sleep at low plasma concentrations and increased sedation at low doses of mirtazapine
• at higher doses, the antihistamine activity is offset by increasing noradrenergic transmission, which reduces its sedating effect
• at very high doses it acts on 5HT3 to have an anti-emetic effect

In order of highest to lowest affinity: H1 (sedation), alpha-2 (antidepressant), 5HT2 (antidepressant), 5HT3 (anti-emetic)

Question 28

What additional side effect is there with venlafaxine that SSRIs do not have?

Answer 28

Venlafaxine is an SNRI so it has the same side effects as SSRIs but with the addition of hypertension (more adrenaline therefore more vasoconstriction –> high BP)